Amino acid derivatives and their therapeutical applications

Abstract

Compounds having the properties of morphinic substances, particularly anasia, with beneficial effects on behaviour and with peripheral effects without their major drawbacks (tolerence, addiction), the blood-brain barrier and having the following formula : H.sub.2 N--CH(R 1 )--CH(R 2 )--S--S--CH(R 3 )--CH(R 4 )--A--B--Z wherein: AB preferably represents a CO amide bond, R 2 et R 3 preferably represent a hydrogen atom, R 1 et R 4 preferably represent, independently of each other, a benzyl grouping, --CH 2 CH 2 SCH 3 , --CH 2 --CH 2 --S(O)--CH 3 or --CH 2 --CH(CH 3 ) 2 , Z may represent a --CH(R 5 )[CH(R 6 )] n --COO(R 7 ) grouping wherein: R 5 may represent a hydrogen atom, a methyl grouping, a benzyl grouping or a phenyl grouping, R 6 may represent a hydrogen atom and may also form a hydrocarbon cycle with R 5 , or Z may represent a heterocyclic grouping, and preferably a morpholinyl grouping. No drawings.

We claim: 
     
       1. A compound of the formula   H.sub.2 N--CH(R.sub.1)--CH(R.sub.2)--S--S--CH(R.sub.3)--CH(R.sub.4)--A--B--Z     in which R 1  is saturated or unsaturated, linear or branched hydrocarbon chain containing from 1 to 6 carbon atoms, unsubstituted or substituted with =OR in which R is hydrogen, a linear or branched C1 to C4 hydrocarbon chain or phenyl or benzyl; =SR, R having the same definition as above, or an oxidized thioether group S(O)R, R having the same definition as above,   methylcycloalkyl of 5 to 6 carbon atoms, benzyl or phenyl optionally substituted: with 1 to 5 halogen,   or OR' or SR', R' being an alkyl group having 1 to 4 carbon atoms, =SR' being optionally oxidized on the sulfur atom,   or with an amino group optionally mono- or disubstituted with an aliphatic of 1 to 6 carbon atoms, optionally oxidized on the amine, R 2  is hydrogen or methyl, R 3  is hydrogen or a linear or branched alkyl chain, R 4  is saturated or unsaturated, linear or branched hydrocarbon chain containing from 1 to 6 carbon atoms, unsubstituted or substituted with a hydroxyl group, =OR in which R has the same meaning as above, =SH, =SR thioether group oxidized to sulfoxide,     or a methylcycloalkyl group having 5 to 6 carbon atoms, a benzyl or phenyl group, optionally substituted with 1 to 5 halogen, with a hydroxyl or a thiol, =OR' or =SR', R' being alkyl of 1 to 4 carbon atoms, the thioether being optionally oxidized on the sulfur atom, with an amino group optionally mono- or disubstituted with an aliphatic of 1 to 6 carbon atoms, optionally oxidized on the amine function,   Z is --CH(R 5 )--CH(R 6 ) n  --COO(R 7 ) in which R 5  and R 6  are individually selected from the group consisting of hydrogen, alkyl group having 1 to 6 carbon atoms, unsubstituted or substituted with hydroxyl or =OR, =SH or =SR groups,   or a phenyl (Phe) or benzyl unsubstituted or substituted with 1 to 5 halogen atoms; =OR' or =SR', R' having the definition specified above,     R 5  and R 6  can also each represent saturated or unsaturated hydrocarbon chains containing from 1 to 6 carbon atoms in which 1 to 2 carbon atoms may be substituted by an oxygen, sulfur or nitrogen atom, capable of leading to the formation of one or more saturated or aromatic 5- to 6-membered hydrocarbon rings, n is 0 or 1,   R 7  is selected from the group consisting of hydrogen, saturated or unsaturated, linear or branched alkyl group having 1 to 6 carbon atoms and benzyl, A--B represents an amide CONH or retro-amide NHCO in the forms of racemic mixtures or in the form of enantiomers, of diastereoisomers or of stereoisomers, as well as mixtures thereof and their non-toxic, pharmaceutically acceptable salts.     
     
     
       2. Compounds according to claim 1 characterized in that Z is   --CH(R.sub.5)--(CH(R.sub.6)).sub.n --COO(R.sub.7)     R 2  and R 3  both are hydrogen, AB is an amide link COHN, R 1  is --CH 2  CH 2  S(O)CH 3  and R 7  is benzyl.   
     
     
       3. Compounds according to claim 2, characterized in that R 4  represents --CH 2  --CH 2  S(O)CH 3 . 
     
     
       4. Compound according to claim 2, corresponding to the formula:   H.sub.2 N--CH(CH.sub.2 CH.sub.2 S(O)CH.sub.3)--CH.sub.2 S--S--CH.sub.2 --CH(CH.sub.2 Phe)CONHCH.sub.2 COOCH.sub.2 Phe     
     
     
       5. Compound according to claim 2, corresponding to the formula: ##STR17## 
     
     
       6. Compound according to claim 3, corresponding to the formula:   H.sub.2 N--CH(CH.sub.2 CH.sub.2 S(O)CH.sub.3)CH.sub.2 --S--S--CH.sub.2 CH(CH.sub.2 CH.sub.2 S(O)CH.sub.3)CONHCH (CH.sub.3)--COOCH.sub.2 Phe.     
     
     
       7. Compound according to claim 3, corresponding to the formula:   H.sub.2 N--CH(CH.sub.2 CH.sub.2 S(O)CH.sub.3)--CH.sub.2 --S--S--CH.sub.2 --CH(CH.sub.2 CH.sub.2 S(O)CH.sub.3)CONHCH (Phe)--CH.sub.2 --COOCH.sub.2 Phe.     
     
     
       8. Compound according to claim 3, corresponding to the formula:   H.sub.2 N--CH(CH.sub.2 CH.sub.2 S(O)CH.sub.3)--CH.sub.2 --S--S--CH.sub.2 --CH(CH.sub.2 CH.sub.2 S(O)CH.sub.3)CONHCH (CH.sub.2 Phe)--CH.sub.2 COOCH.sub.2 Phe.     
     
     
       9. Compound according to claim 3, corresponding to the formula: ##STR18## 
     
     
       10. Compound according to claim 1, corresponding to the formula:   H.sub.2 NCH(CH.sub.2 CH.sub.2 SCH.sub.3)CH.sub.2 S--S--CH.sub.2 CH(CH.sub.2 CH(CH.sub.3).sub.2)CONHCH(CH.sub.3) COOCH.sub.2 Phe.     
     
     
       11. Compound according to claim 1, corresponding to the formula:   H.sub.2 NCH(CH.sub.2 CH.sub.2 SCH.sub.3)CH.sub.2 --S--S--CH.sub.2 --CH(CH.sub.2 CH.sub.2 SCH.sub.3)CONHCH(CH.sub.3) COOCH.sub.2 Phe.     
     
     
       12. Compound according to claim 1, corresponding to the formula:   H.sub.2 N--CH(CH.sub.2 CH(CH.sub.3).sub.2)--CH.sub.2 --S--S--CH.sub.2 --CH(CH.sub.2 Phe)CONH--CH.sub.2 COOCH.sub.2 Phe.     
     
     
       13. Compound according to claim 1, corresponding to the formula:   H.sub.2 N--CH(CH.sub.2 CH(CH.sub.3).sub.2)--CH.sub.2 --S--S--CH.sub.2 --CH(CH.sub.2 Phe)CONH--CH(CH.sub.3) COOCH.sub.2 Phe.     
     
     
       14. Compound according to claim 1, corresponding to the formula:   H.sub.2 N--CH(CH.sub.2 CH(CH.sub.3).sub.2)--CH.sub.2 --S--S--CH.sub.2 --CH(CH.sub.2 Phe)CONH--CH(CH.sub.2 Phe) --COOCH.sub.2 Phe.     
     
     
       15. Compound according to claim 1, corresponding to the formula:   H.sub.2 N--CH(CH.sub.2 CH.sub.2 SCH.sub.3)--CH.sub.2 --S--S--CH.sub.2 --CH(CH.sub.2 Phe)CONH--CH.sub.2 --COOCH .sub.2 Phe.     
     
     
       16. Compound according to claim 1, corresponding to the formula:   H.sub.2 N--CH(CH.sub.2 CH.sub.2 SCH.sub.3)--CH.sub.2 --S--S--CH.sub.2 --CH(CH.sub.2 Phe)CONH--CH(CH.sub.3) COOCH.sub.2 Phe.     
     
     
       17. Compound according to claim 1, corresponding to the formula:   H.sub.2 N--CH(CH.sub.2 CH.sub.2 SCH.sub.3)CH.sub.2 --S--S--CH.sub.2 --CH(CH.sub.2 Phe)CONH--CH(CH.sub.2 Phe) COOCH.sub.2 Phe.     
     
     
       18. Compound according to claim 1, corresponding to the formula:   H.sub.2 N--CH(CH.sub.2 CH.sub.2 S(O)CH.sub.3)--CH.sub.2 --S--S--CH.sub.2 --CH(CH.sub.2 Phe)--CONH--CH (CH.sub.2 Phe)--COOCH.sub.2 Phe.     
     
     
       19. A method of relieving pain in warm-blooded animals comprising administering to warm-blooded animals an analgesically effective amount of a compound of claim 1. 
     
     
       20. An analgesic composition comprising an analgesically effective amount of a compound of claim 1 and an inert pharmaceutical carrier.